Food allergy has become a major health problem in westernized countries and now affects 3.5% - 4% of the U.S. population with cow's milk allergy [CMA] affecting 2.5% of young children. CMA provides an ideal model to study immunologic mechanisms responsible for allergic disease and tolerance induction. It is a common food allergic disorder that reflects both the "transient" form of food allergy that is "outgrown," as seen in many other childhood food allergies [e.g. egg, soy, wheat], and the "persistent," more severe form, similar to life-long peanut, tree nut and seafood allergies. Diagnosis is definitive with the blinded food challenge, the responsible allergens [milk proteins] are well characterized including their 3-dimensional structures, and good animal models have been established that enable dissection of immunologic and systemic mechanisms at the molecular level. Over the past granting period, we demonstrated that the majority of children with IgE-mediated CMA can safely ingest baked [heat-denatured] milk products without adverse effects and identified a variety of immunologic markers [humoral and cellular] that distinguish them from the minority of children with persistent CMA who cannot tolerate any form of milk protein. Using animal models and epithelial cell lines, it was shown that IgE and CD23 are required for enhanced allergen uptake in the small intestine and are found in the stool of food-allergic but not non-allergic children, supporting their role in the allergic diathesis as well as their potential for use as a biomarker of clinical food allergy. Studies in a murine model of CMA also showed that the way specific milk proteins traffick in the Gl mucosa may play a critical role in the ultimate response of the host;i.e. immunologic tolerance vs. allergen sensitization and clinical tolerance vs. allergic reaction. Based on knowledge acquired in our previous Center grant, we will further explore clinical and underlying immunologic responses in one clinical trial examining the effects of graded exposure to heat-denatured milk products, and in a second clinical trial of milk oral immunotherapy [OIT] plus omalizumab, which we hypothesize will induce "tolerance," as opposed to "desensitization" seen with standard milk OIT. We also will use novel models to delineate properties that make certain milk proteins allergenic, explore how they are processed at the cellular level, and define the role of facilitated CD23 transport in food allergic disease. Through the unique resources and collaborative projects outlined in this Center application, successful completion of the aims may lead to new paradigms in the management and treatment of food allergies and provide novel biomarkers for the diagnosis and management of patients.